sciences

Review The Role of Sartans in the Treatment of and : A Narrative Review of Preclinical and Clinical Studies

Stefan Wanderer 1,2,*, Basil E. Grüter 1,2 , Fabio Strange 1,2 , Sivani Sivanrupan 2 , Stefano Di Santo 3, Hans Rudolf Widmer 3 , Javier Fandino 1,2, Serge Marbacher 1,2 and Lukas Andereggen 1,2

1 Department of Neurosurgery, Kantonsspital Aarau, 5001 Aarau, Switzerland; [email protected] (B.E.G.); [email protected] (F.S.); [email protected] (J.F.); [email protected] (S.M.); [email protected] (L.A.) 2 Cerebrovascular Research Group, Neurosurgery, Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland; [email protected] 3 Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; [email protected] (S.D.S.); [email protected] (H.R.W.) * Correspondence: [email protected] or [email protected]; Tel.: +41-628-384-141

 Received: 17 January 2020; Accepted: 5 March 2020; Published: 7 March 2020 

Abstract: Background: Delayed cerebral (DCVS) due to aneurysmal subarachnoid hemorrhage (aSAH) and its sequela, delayed cerebral (DCI), are associated with poor functional outcome. Endothelin-1 (ET-1) is known to play a major role in mediating cerebral vasoconstriction. Angiotensin-II-type-1-receptor antagonists such as Sartans may have a beneficial effect after aSAH by reducing DCVS due to crosstalk with the endothelin system. In this review, we discuss the role of Sartans in the treatment of stroke and their potential impact in aSAH. Methods: We conducted a literature research of the MEDLINE PubMed database in accordance with PRISMA criteria on articles published between 1980 to 2019 reviewing: “Sartans AND ischemic stroke”. Of 227 studies, 64 preclinical and 19 clinical trials fulfilled the eligibility criteria. Results: There was a positive effect of Sartans on ischemic stroke in both preclinical and clinical settings (attenuating ischemic , reducing cerebral inflammation and infarct size, increasing cerebral blood flow). In addition, Sartans reduced DCVS after aSAH in animal models by diminishing the effect of ET-1 mediated vasoconstriction (including cerebral inflammation and cerebral epileptogenic activity reduction, cerebral blood flow autoregulation restoration as well as pressure-dependent cerebral vasoconstriction). Conclusion: Thus, Sartans might play a key role in the treatment of patients with aSAH.

Keywords: aneurysmal subarachnoid hemorrhage; delayed cerebral vasospasm; ischemic stroke; Sartans; therapeutic interventions

1. Introduction Aneurysmal subarachnoid hemorrhage (aSAH) induces delayed cerebral vasospasm (DCVS) [1], cerebral inflammation [2,3], early brain injury [4], cortical spreading depression [5], delayed cerebral ischemia (DCI) [6], and lack of cerebral autoregulation [7] contributing to poor functional patients’ outcome. DCVS remains a major cause of patient’s morbidity and mortality by inducing delayed cerebral ischemia [8].

Brain Sci. 2020, 10, 153; doi:10.3390/brainsci10030153 www.mdpi.com/journal/brainsci Brain Sci. 2020, 10, 153 2 of 25

Multiple studies showed that endothelin-1 (ET-1), a most potent vasoconstrictor [9–11], plays a key role in the development of DCVS [12–19]. Although endothelin-A-receptor (ETA-R) antagonists in the treatment of DCVS in animal models are effective [10,20], clinical studies did not show beneficial effects [21,22]. It has been reported that the polypeptide angiotensin-II acts through two specific receptors, in essence the angiotensin-II-type-1- and angiotensin-II-type-2-receptor (AT2-1-R and AT2-2-R). Important to note is that activation of the AT2-1-R results in vasoconstriction while binding of angiotensin-II to the AT2-2-R causes vasorelaxation [23]. In line with this notion, preclinical as well as clinical trials showed promising results of Sartans, which are AT2-1-R antagonists, in ischemic stroke. Hence, Sartans may have a positive effect after aSAH by reducing DCVS due to crosstalk with the endothelin system. Thus, we aimed to analyze the potential role of Sartans in the treatment of aSAH.

2. Materials and Methods We conducted a systematic literature research of the MEDLINE PubMed database in accordance with PRISMA guidelines on preclinical studies on the one and on clinical studies on the other hand published between 1980 to 2019 reviewing: “Sartans and ischemic stroke” [24]. Only articles in English were chosen for review. Search items with “Sartans” (n = 19,064) and “ischemic stroke” (n = 89,465) were extracted. For “Sartans AND ischemic stroke”, 227 publications met the inclusion criteria by excluding studies with commentary only, any duplicates, or results not commenting on cerebral effects of Sartans. Two hundred and twenty-seven studies were assessed for eligibility, 83 met inclusion criteria for systematic review and qualitative analysis with 64 preclinical studies (Figure1 demonstrates the inclusion pathway for basic research studies selected via MEDLINE PubMed search) and 19 clinical studies (Figure2 shows the inclusion pathway for clinical research studies selected via MEDLINE

PubMed search).Brain Sci. 2020, 10, x FOR PEER REVIEW 3 of 23

Figure 1. TwoFigure hundred 1. Two and hundred twenty-seven and twenty-seven articles articles (published (published 01-01-1980–01-07-2019) 01-01-1980–01-07-2019) were detected were detected for preclinical andfor clinical preclinical research and clinical articles. research After articles. manual After manual abstract abstract screening screening for for preclinical preclinical research research articles articles only, 79 articles remained for further analysis. Each of the 79 articles was explicitly screened only, 79 articlesfor remained potential drug for applications further analysis. after ischemic Each stroke. of theFinally, 79 64 articles articles waswere included explicitly for qualitative screened for potential drug applicationsanalysis. after ischemic stroke. Finally, 64 articles were included for qualitative analysis. Brain Sci. 2020, 10, 153 3 of 25 Brain Sci. 2020, 10, x FOR PEER REVIEW 4 of 23

FigureFigure 2. 2.Two Two hundred hundred and and twenty-seven twenty-seven articles articles (published (published 01-01-1980–01-07-2019) 01-01-1980–01-07-2019) were were detected detected for preclinicalfor preclinical and clinical and clinical research research articles. articles. After manualAfter manual abstract abstract screening screening for clinical for clinical research research articles only,articles 46 articlesonly, 46remained articles remained for further for further analysis. analysis. Each ofEach the of 46 the articles 46 articles was was explicitly explicitly screened screened for potentialfor potential drug applicationsdrug applications afterischemic after ischemic stroke. stroke. Finally, Finally, 19 articles 19 werearticles included were included for final analysis.for final analysis. Of the articles included in the final analysis, a systematic review on the beneficial and non-beneficial eff3.ect Results in the preclinical and clinical settings was performed. Summary measures are reported as outcome measures (i.e., infarct size, neurocognition, inflammation). 3.1. Preclinical Studies on Sartans in Animal Models of Ischemic Stroke 3. Results The search finally yielded 64 preclinical studies on “Sartans AND ischemic stroke”, eligible for 3.1.systematic Preclinical review Studies (Table on Sartans 1). in Animal Models of Ischemic Stroke The search finally yielded 64 preclinical studies on “Sartans AND ischemic stroke”, eligible for systematic review (Table1). Brain Sci. 2020, 10, 153 4 of 25

Table 1. Tabular listing of different preclinical studies showing various effects of Sartan administration (Abbreviations: Angiotensin-II-type-1-receptor (AT2-1-R); Angiotensin-II-type-2-receptor (AT2-2-R); common carotid artery occlusion (CCAO); chemokine receptor 2 (CCR2); cluster of differentiation (CD); candesartan (CS); desoxy ribonucleic acid (DNA); endothelial nitric oxide synthase (eNOS); endothelin-A-receptor (ETA-R); hours (h); inducible nitric oxide synthase (iNOS); irbesartan (IS); kilogram (kg); losartan (LS); middle cerebral artery occlusion (MCAO); matrix-metallo-proteinase (MMP); messenger ribonucleic acid (mRNA); milligram (mg); minutes (min); n-acetyl-glucosamine oligomer (NAGO); nlr family pyrin domain containing 3 (NLRP3); glucose deprivation (OGD); olmesartan (OMS); stroke-resistant spontaneously hypertensive rats (SR-SHR); telmisartan (TMS); tumor necrosis factor alpha (TNFα); ribonucleic acid (RNA); vascular endothelial growth factor (VEGF); valsartan (VS)).

Drug Model Outcome Beneficial Effect Special Remarks TMS [25] Global ischemic mice model Cerebral Restored cerebral blood flow - Improved neuroscore and decreased infarct size, TMS [26] MCAO mice Neuroscore, infarct size increased cerebral blood flow, reduced superoxide - production and inflammatory cytokine expression Murine model of Reduced stroke volume 72 h after transient ischemia, Infarct size, No reduction in stroke volume 72 h TMS [27] transient and permanent likewise pro-inflammatory adhesion molecules and after permanent ischemia focal ischemia infiltration of inflammatory cells in the ischemic region Attenuated ischemic brain damage, neurological deficits and superoxide production in ischemic area; Focal brain ischemia, TMS [28] MCAO mice attenuated reduction of cerebral blood flow in the Anti-atherosclerotic effects atherosclerotic lesions without significantly changing blood pressure Improved cerebral blood flow, enhanced vascular TMS [29] MCAO rat Cerebral perfusion density (CD31 immunofluorescence staining), - antiapoptotic effects Cognitive function, Improved spatial memory ability, decreased TMS [30] MCAO rat level of matrix - expression levels of MMP-2 and MMP-9 metalloproteinases Behavior alterations, Normalized behavioral alterations comparable to In combination with nimodipine. neuroprotective effects pre-ischemic treatment (protected neurons from Drug treatments immediately after TMS [31] MCAO rat on secondary ischemic reperfusion injury), attenuated excitatory reperfusion, effects compared reperfusion phase amino acid release in secondary reperfusion phase with pretreatment Brain Sci. 2020, 10, 153 5 of 25

Table 1. Cont.

Drug Model Outcome Beneficial Effect Special Remarks Low dose TMS improved changes Effects on neurovascular Reduced decrease of NAGO-positive endothelium, without lowering blood pressure, TMS [32] MCAO rat unit and similar increase of MMP-9 positive neurons and high dose TMS further improved neuroinflammation NLRP3-positive inflammasome in the changes with lowering blood pressure Cerebral arteriolar pressure, cerebral blood Normalization of arteriolar pressure and lower limit TMS [33] Open skull preparation rat Combined with Ramipril flow, internal of cerebral autoregulation vessel diameter Metabolic related TMS [34] MCAO rats Ameliorated metabolic related post-ischemic changes - post-ischemic changes Neurological outcome, Subcutaneous TMS application 5 Improved outcome, reduced infarct volume TMS [35] MCAO rats infarct volume, days prior to MCAO and inflammation inflammation with reperfusion Infarct volume, Significantly reduced infarct volume, reduced TMS [36] MCAO rats immunohistochemical neurotoxic cytosolic phospholipase A2, ameliorates Pretreatment for 7 days parameters ischemic changes of neurons in the peri-infarct area Collagenase infusion or Reduced hemorrhage volume, brain edema, autologous blood injection Hemorrhage volume, inflammatory/apoptotic cells in perihematomal area; TMS [37] - to induce intracerebral functional recovery induced endothelial nitric-oxide-synthase, decreased hemorrhage in rats oxidative stress, apoptotic signals, and TNFα Reduced advanced glycation end product, Stroke-resistant 4-hydroxy-2-nonenal- and phosphorylated TMS [38] spontaneously Oxidative stress - a-synuclein-positive cells in the cerebral cortex hypertensive rats and hippocampus Reduced ischemic brain area and neurological deficits in non-hypotensive doses; improved reduction of brain surface blood flow and inhibited superoxide CS [39] MCAO mice Ischemic brain damage production in the cortex and brain arterial wall at - non-hypotensive and hypotensive doses; AT2-2-R expression in the ischemic area was increased by prior pretreatment with CS Brain Sci. 2020, 10, 153 6 of 25

Table 1. Cont.

Drug Model Outcome Beneficial Effect Special Remarks Antioxidant enzyme Restored superoxide dismutase activity and cerebral CS [40] MCAO mice - activity blood flow Neurobehavioral In vitro vascular density was Improved neurobehavioral outcome, reduced infarct CS [41] MCAO rats outcome, infarct size, assessed using size and vascular density vascular density endothelial cells Infarct size, Improved neurobehavioral and motor functions, CS [42] MCAO rats Intravenous CS administration neurological outcome decreased infarct size Only 0.3 mg/kg CS with CS [43] MCAO rats Neurological outcome Improved recovery from ischemic stroke neuroprotective function Neurological outcome, Improved motor function and reduced endoplasmatic CS [44] MCAO rats Only early beneficial effect after 24 h oxidative enzymes reticulum stress markers Intracerebroventricular injection of Neurological outcome, short hairpin RNA lentiviral Improved functional outcome, increased vascular CS [45] MCAO rats vascular particles to knock down density/synaptogenesis only in the control group density/synaptogenesis brain-derived neurotrophic factor or nontargeting control vector Induced prolonged proangiogenic effect and upregulation of VEGF-A and VEGF-B; CS [46] MCAO rats Angiogenesis - stabilized hypoxia-inducible factor-1a and preserves angiopoetin-1 Spontaneously Exerted proangiogenic effects on brain microvascular CS [47] Angiogenesis - hypertensive rats endothelial cells In vitro monolayer model Stability of blood Improved cell function and viability of brain capillary CS [48] using rat brain capillary Normoxia versus 6 h OGD brain barrier endothelial cells under OGD endothelial cells Neurological outcome, Improved neurological function, significantly reduced CS [49] MCAO rats - infarct size blood brain barrier disruption/edema/infarct volume Significantly reduced infarct size, ameliorated Infarct size, functional CS [50] MCAO rats functional recovery and increased - recovery, neuroplasticity neuroplasticity markers Brain Sci. 2020, 10, 153 7 of 25

Table 1. Cont.

Drug Model Outcome Beneficial Effect Special Remarks Infarct size, Decreased infarct size and improved CS [51] MCAO rats - neurological outcome neurological outcome CS [52] MCAO rats Mortality, infarct size Significantly reduced mortality and infarct size - CS [53] MCAO rats Infarct size Reduced infarct size Oral administration Infarct size, edema, Reduced infarct size, edema formation and improves CS [54] MCAO rats - neurological outcome neurological outcome Infarct size, Significantly reduced stroke volume and improved CS [55] MCAO rats - neurological outcome neurological outcome Reduced infarct size and edema, improved CS [56] MCAO rats Infarct size, edema - neurologic function Infarct volume, Reduced infarct size and improved CS [57] MCAO rats - neurological deficit neurologic outcome Infarct volume, Reduced infarct size, improved neurological outcome, CS [58] MCAO rats Subcutaneous infusion for 14 days neurological deficits reduced lipid peroxidation Long-term blockade (subcutaneous injection twice daily 5 days before Infarct volume, Reduced infarct size/edema and improved ischemia), not short-term CS [59] MCAO rats neurological deficits neurological outcome administration (intravenous once 4 h prior to ischemia), improves neurological outcome Infarct volume, Significantly reduced cortical infarct volume and CS [60] MCAO rats - brain edema brain edema Attenuated neurobehavioral alterations, oxidative Occlusion for 30 min, followed by Neurological outcome, CS [61] Bilateral CCAO rats damage and restored mitochondrial 24 h reperfusion; CS pretreatment oxidative damage enzyme dysfunction for 7 days CS [62] MCAO rats Infarct size Reduced infarct area - Infarct size, Pretreatment reduced infarct area and improved CS [63] MCAO rats - neurological outcome neurological outcome Reduced infarct size and neurological deficits; Infarct size, CS [64] MCAO rats significantly reduced mRNA expression of - neurological outcome inflammatory markers Brain Sci. 2020, 10, 153 8 of 25

Table 1. Cont.

Drug Model Outcome Beneficial Effect Special Remarks Spontaneously Increased AT -2-R expression in spontaneously CS application via subcutaneous CS [65] AT -1-R expression 2 hypertensive rats 2 hypertensive rats osmotic minipumps for 4 weeks Neurological outcome, Improved neurological outcome and increased CS [66] MCAO rats - vascular density vascular density Mortality, neurological Significantly decreased mortality, neurological deficits, CS [67] Embolic stroke model Injection of calibrated microspheres outcome, infarct size and infarct size Infarct size, Reduced infarct size and improved Combined treatment with CS [68] MCAO rat neurological outcome neurological outcome ETA-R antagonist Contractile response to CS [69] MCAO rats Abolished the enhanced responses to angiotensin II - angiontensin II Infarct volume, Reduced infarct size with low but not high dose of CS, CS [70] MCAO rats Subcutaneous CS administration neurological outcome improved neurological outcome Infarct size, neuroscores, CS [71] MCAO rats Reduced infarct size and increased cerebral blood flow Intravenous CS administration cerebral blood flow Vascular remodeling, Spontaneously Reversed negative vascular remodeling and CS [72] expression - hypertensive rats alterations in eNOS/iNOS expression of eNOS/iNOS OMS [73] Bilateral CCAO mice Cognitive impairment Ameliorated cognitive impairment - Single carotid ligation stroke OMS [74] Survival Significantly increased survival at day 30 - model gerbil Only continuous administration of Neurological outcome, Significantly improved functional scores, reduced OMS [75] MCAO rats OMS before and after stroke infarct size, cell infarct size and reduced oxidative stress levels Reduced infarct volume 48 h after transient focal OMS administration via OMS [76] MCAO rats Infarct volume brain ischemia drinking water Stroke index score, Improved stroke index score, infarct volume, OMS [77] MCAO rats infarct volume, - reduced and upregulation of MMPs quantity of MMPs Brain Sci. 2020, 10, 153 9 of 25

Table 1. Cont.

Drug Model Outcome Beneficial Effect Special Remarks Significantly reduced infarct size, DNA damage, Infarct volume, superoxide production, mRNA levels of monocyte VS [78] MCAO mice DNA damage, chemoattractant protein-1, increases cerebral blood - superoxide production flow, increased eNOS activation and nitric oxide production Infarct volume, Significantly reduced infarct volume and improved VS [79] MCAO mice - neurological outcome neurological outcome Significantly reduced ischemic area, neurological Infarct volume, VS [80] MCAO mice deficits, reduction of cerebral blood flow and - neurological outcome superoxide production Enhanced protective effects against brain injury, white VS [81] High salt loaded SR-SHR Brain injury Combined with amlodipine matter lesions and glial activation Reduced infarct size and number of apoptotic cells in Infarct size, the peri-infarct cortex on day 3, attenuated invasion of IS [82] MCAO rats - neurological outcome microglia and macrophages on day 3 and 7 after ischemia Administration of IS IS [83] MCAO rats Neurological outcome Significantly improved neurological outcome intracerebroventricularly over 5 days Coadministration of IS [84] MCAO rats Infarct size Reduced infarct volume propagermanium (CCR2 antagonist) Single carotid ligation stroke Did not increase mortality after unilateral carotid LS [85] Mortality - model gerbil ligation in gerbils Abolished OGD-induced exaggeration of cell injury in LS [86] MCAO mice OGD-induced cell injury mice overexpressing renin and - angiotensinogen animals Gene expression levels Significant reduced gene expression of LS [87] MCAO rats - of pro-apoptotic genes pro-apoptotic genes Cerebral focal ischemia by Administration of LS in drinking Cessation of blood flow, Maintained angiogenesis, vascular delivery, LS [88] cauterization of cortical water 2 weeks before infarct size and significantly decreased infarct size surface vessels rats inducing ischemia Brain Sci. 2020, 10, 153 10 of 25

Telmisartan (TMS), a selective AT2-1-R antagonist, displayed the capacity to increase cerebral blood flow (CBF) in global cerebral ischemia [25]. It ameliorated reduction of CBF in the penumbra (0.3 mg/kg/day) without significant changes in blood pressure (BP) [28]. Following middle cerebral artery occlusion (MCAO), TMS decreased ischemic infarct area, reduced superoxide production and expression of inflammatory cytokines, infiltration of inflammatory cells, improved neurological scores, and increased CBF [26,27]. Angiogenesis in ischemic areas after MCAO was enhanced by TMS, as well as neuroregeneration by downregulating caspase activation [29]. A combination of TMS with nimodipine (2.5–5 mg/kg) in a transient MCAO rat model revealed beneficial influences affecting the attenuation of excitatory amino acids in different brain regions nine days after MCAO with neurobehavioural outcomes normalized seven days after MCAO [31]. Low doses of TMS (0.3–3 mg/kg/d) after MCAO in a model of stroke-resistant spontaneously hypertensive rats (SR-SHR) reduced progressive decrease of N-acetylglucosamine oligomer and increase of MMP-9 positive neurons without reducing BP [32]. Likewise combination therapies with ramipril (0.8 mg/kg per day TMS + 0.1 mg/kg per day ramipril or 0.5 mg/kg per day TMS + 0.25 mg/kg per day ramipril) normalized BP as well as maintained cerebral blood flow autoregulation [33]. Deguchi et al. demonstrated that TMS dose-dependently (0.3 mg/kg/day or 3 mg/kg/day) ameliorated metabolic syndrome related changes in the post stroke brain of SR-SHR with direct neuroprotective effects [34]. Moreover, incidence of stroke was reduced along with prolonged survival and improved neurological outcome following TMS application (0.5 mg/kg once daily)[35]. Pretreatment of rats with TMS (1 mg/kg) seven days before inducing cerebral ischemia also showed significant reduced infarct size and histopathologically normal appearance of neurons in the periinfarct cortical regions [36]. Candesartan (CS), another AT2-1-R antagonist, reduced ischemic brain damage following MCAO occlusion [39]. CS and curcumin together significantly restored superoxide dismutase activity and blood flow compared with the untreated group [40]. Further, CS upregulated vascular endothelial growth factor (VEGF) B after induction of focal cerebral ischemia using a MCAO model. In contrast to saline-treatment after reperfusion, CS further improved neurobehavioral and motor functions and decreased infarct size [41]. VEGF-B silencing was shown to diminish CS (1 mg/kg) protective effects [42]. CS (0.3 mg/kg) was able to improve recovery from ischemic stroke in low doses by maintaining blood pressure during reperfusion [43]. CS induced early protective effects with improvement in motor function, upregulated brain-derived neutrotrophic factor (BDNF), and also reduced endoplasmatic reticulum stress markers [44]. In a MCAO BDNF, knock-out model rats received CS or saline at reperfusion for 14 days, revealing better functional outcomes, increased vascular density, and synaptogenesis in the CS (1 mg/kg) group [45,46]. In addition, CS (0.16 µM) significantly increased BDNF production [47]. Furthermore, CS (10 nM) improved cell function and viability of brain capillary endothelial cells under oxygen glucose deprivation, providing protective blood–brain-barrier (BBB) effects [48]. In other transient MCAO rat models, CS (0.1 mg/kg; 0.3 mg/kg; 1.5 or 10 mg/kg per day; 0.1, 1 and 10 mg/kg; 0.1, 0.3 or 1 mg/kg; 0.1 mg/kg twice daily; 1 mg/kg; 0.3 or 3 mg/kg per day; 0.5 mg/kg per day for 14 days; 0.1 or 0.3 mg/kg; 0.5 mg/kg per day for 3 to 14 days) showed improved neurological function with significant reduction in BBB disruption, in cerebral ischemia, and in edema [39,49–60]. In a bilateral common carotid artery occlusion (CCAO) model in rats, pretreatment with CS (0.1 and 0.3 mg/kg) and atorvastatin significantly attenuated neurobehavioral alterations, oxidative damage, and restored mitochondrial enzyme dysfunction compared to the control group [61,62]. AT2-1-R administration prior to ET-1 induced MCAO provides neuroprotective effects, with CS (0.2 mg/kg per day for seven days) pretreatment attenuating infarct size and neurological deficits without altering systemic BP [63]. Pretreatment with CS for five days significantly decreased mortality, neurological deficits, and infarct size [67]. A combined inhibition of AT2-1- (0.05 mg/kg per day) and ETA-receptors decreased brain damage as well; additionally, an upregulation of AT2-1-R in ischemic middle cerebral artery smooth muscle cells (SMCs) was found [68,69]. Also, early (3 h) and delayed (24 h) effects of CS treatment (0.3 and 3 mg/kg) continued for seven days after onset of MCAO with reperfusion in normotensive rats involved a reduction of the infarct volume by low doses of CS [70]. Brain Sci. 2020, 10, 153 11 of 25

CBF in CS (0.5 mg/kg) pretreated animals at 0.5 h after MCAO was significantly increased compared to the control group [71]. Other groups additionally showed a four-week CS-pretreatment (0.3 mg/kg per day) before MCAO clearly associated with complete reversal of a decreased lumen diameter and increased media thickness as well as decreased endothelial nitric oxide synthase (eNOS) and increased inducible nitric oxide synthase (iNOS) protein and mRNA in SR-SHR and in a normotensive control group [72]. Olmesartan (OMS), an AT2-1-R antagonist, has been evaluated in a bilateral CCAO model in mice, revealing improved cognitive outcome, neuroprotective effects, attenuation of oxidative hippocampal stress, and suppression of BBB disruption compared to control groups [73]. A single carotid ligation stroke model in gerbils showed that OMS (10 mg/kg per day started 36 h after stroke) was associated with an increased survival [74]. Other studies demonstrated that OMS (10 mg/kg per day for 14 days after infarct; 10 mg/kg per day for 7 days before and 14 days after infarct; 10 mg/kg per day for 7 days before infarct) treatment in a rat MCAO model showed significantly better functional scores and reduced infarct size and cell death [75]. OMS (0.01 or 0.1 µmol/kg per hour for seven days) reduced brain angiotensin II, MMP-2 and MMP-9 upregulation following brain ischemia [77]. Valsartan (VS), a selective AT2-1-R antagonist, reduced ischemic brain area and improved the neurological deficit after MCAO with restoration of cerebral blood flow [78]. VS significantly reduced infarct volume and improved the neurological deficit scores. VS at nonhypotensive doses significantly diminished ischemic area, neurological deficits, and reduction of cerebral blood flow as well as superoxide production [27,78,80]. Irbesartan (IS), a selective AT2-1-R antagonist improved motor functions, reduced infarct size and decreased the number of apoptotic cells particularly in the periinfarct area by attenuated invasion of activated microglia likewise macrophages [82–84]. Losartan (LS), a clinical established selective AT2-1-R antagonist, did not increase mortality in acute cerebral ischemia [85]. Also, LS (20 µmol/L) abolished ischemic exaggeration of cell injury [26,86]. Expression levels of pro-apoptotic genes were significant reduced by LS treatment [87]. Further LS administration initiates cerebral angiogenic response with a significantly larger vessel surface area, and administration before initiation of cerebral focal ischemia (50 mg/day for 2 weeks) markedly reduces infarct size [88].

3.2. Clinical Studies on Sartans in Ischemic Stroke The search yielded 19 clinical studies on “Sartans AND ischemic stroke”, eligible for systematic review (Table2). Beneficial aspects of using AT 2-1-R antagonists before the onset of ischemic stroke have already been elucidated in a retrospective analysis of 151 patients [89].

Table 2. Tabular listing of different clinical studies showing various effects of Sartan administration (Abbreviations: Candesartan (CS); hours (h); losartan (LS); milligram (mg); minutes (min); µmol (micromolar); modified ranking Scale (mRS); mol (molar); nmol (nanomolar); telmisartan (TMS); valsartan (VS)).

Drug Outcome Beneficial Effect Special Remarks No overall effect on vascular events in Administration at least within 30 h of Vascular event (vascular death, ischemic and/or hemorrhagic stroke, ischemic or hemorrhagic stroke. CS CS [90] nonfatal stroke or nonfatal myocardial adjusted odds ratio for vascular events of treatment for 7 days, increasing from ) over 6 months and mRS patients treated within 6 h 4 mg on day 1 to 16 mg on day 3 to 7 reached significance Administration at least within 30 h of Barthel index and level of care No significant effects on Barthel Index or ischemic or hemorrhagic stroke. CS CS [91] assessed after 6 months level of care at 6 months treatment for 7 days, increasing from 4 mg on day 1 to 16 mg on day 3 to 7 Significant trend towards a better effect of Vascular death, , CS treatment for 7 days, increasing CS in patients with larger infarcts; no CS [92] stroke during first 6 months and from 4 mg on day 1 to 16 mg differences in treatment effect for composite functional outcome at 6 months on day 3 to 7 vascular end point Brain Sci. 2020, 10, 153 12 of 25

Table 2. Cont.

Drug Outcome Beneficial Effect Special Remarks Vascular death, myocardial infarction, After 6 months the risk of the composite CS treatment for 7 days, increasing CS [93] stroke during first 6 months and vascular endpoint did not differ between from 4 mg on day 1 to 16 mg functional outcome at 6 months treatment groups on day 3 to 7 CS treatment with 4 mg on day 1; The cumulative 12 months mortality and Safety of modest blood pressure dosage increased to 8 mg on day 2 or the number of vascular events differed CS [94] reduction by CS cilexetil in the early 16 mg if blood pressure exceeded significantly in favor of the treatment of stroke 160 mmHg systolic or CS cilexetil group 100 mmHg diastolic Short-term safety of blood pressure CS treatment safely reduces blood pressure CS [95] reduction in hypertensive patients in hypertensive patients with acute 4 mg/day for 14 days with acute ischemic stroke ischemic stroke CS inhibited the adhesion of neutrophils to Adhesion of neutrophils to human vascular endothelium in ischemic stroke CS [96] endothelial cells in acute Incubation with 10 9 mol for 30 min patients (not in chronic stroke patients or − ischemic stroke healthy volunteers) Effect of blood pressure lowering in patients with acute ischemic stroke No evidence that CS effect is qualitatively CS treatment for 7 days, increasing CS [97] and (Vascular different in patients with carotid from 4 mg on day 1 to 16 mg death, stroke, myocardial infarction, artery stenosis on day 3 to 7 and functional outcome at 6 months) 80 mg/day (dose was modified in the Safety of modest blood pressure After 90 days the mRS as well the rate of subsequent six-days of treatment if VS [98] reduction within 48 h of acute major vascular events differed not the target systolic blood pressure was ischemic stroke significantly between both groups not achieved) VS exhibited significant inhibition of Effect of vs. on human VS [99] human platelets and therefore might be 10 nmol to 100 µmol platelet aggregation able to reduce vascular ischemic events Low glomerular filtration rate (<60 mL/min) is independently associated with a TMS [100] Time to first recurrent stroke TMS dosage not reported higher risk of recurrent stroke, TMS not able to mitigate this risk Similar rates of recurrent comparing TMS [101] Recurrent stroke of any type aspirin plus extended-release dipyridamole 80 mg/day with clopidogrel and TMS TMS on top of existing antihypertensive Prevention of cerebral white 80 mg/day. Analysis limited by the TMS [102] medication did not prevent the progression matter lesions relatively short follow-up of white matter lesions Functional outcome at 30 days TMS treatment appears to be safe with no (primary outcome), death, recurrence, excess in adverse events and not associated TMS [103] 80 mg/day and hemodynamic measures up to with a significant effect on functional 90 days (secondary outcomes) dependency, death, or stroke recurrence TMS initiated soon after ischemic stroke and continued for 2.5 years did not TMS [104] Recurrent stroke significantly lower the rate of recurrent 80 mg/day stroke, major cardiovascular events, or diabetes LS treatment increases the global cerebral LS [105] Global change of cerebral blood flow 50–100 mg/day for 4 weeks blood flow despite blood pressure lowering Incidence of any stroke (40% risk reduction), fatal stroke (70% risk reduction), Effect on stroke in patients with and atherothrombotic stroke (45% risk LS [106] isolated systolic hypertension and left Mean LS dose of 79 mg reduction) was significantly lower in the ventricular hypertrophy LS treated group compared to atenolol treated patients Effect on global and focal cerebral No neurological deterioration in the LS [107] blood flow in hypertensive patients 25–50 mg/day LS group 2–7 days after stroke Spontaneous platelet aggregation and Spontaneous platelet aggregation was not, P-selectin levels (in patients with P-selectin levels significantly reduced after LS [108] 50 mg/day hypertension and chronic LS treatment. This suggests that standard ischemic stroke) doses of LS display antiplatelet effect

CS has been evaluated in the Scandinavian Candesartan Acute Stroke Trial (SCAST). Within 30 h of ischemic or hemorrhagic stroke, 2029 patients either received CS- or placebo-treatment. The modified ranking Scale (mRS) was used for outcome analysis. CS showed no overall effect on vascular events in ischemic and/or hemorrhagic stroke, and the adjusted odds ratio for vascular events of patients Brain Sci. 2020, 10, 153 13 of 25 treated within 6 h reached significance [90]. At six months, activities of daily living and level of care were assessed. In more than 1800 patients, over 1500 suffered ischemic and almost 250 hemorrhagic strokes. No statistically significant effects of CS on Barthel index or level of care could be identified [91]. Furthermore, the SCAST group evaluated whether the effect of CS treatment varies in subtypes of over 1700 ischemic strokes. Concerning functional outcomes, a trend towards a beneficial effect of CS was observed in patients with larger infarcts (total anterior circulation or partial anterior circulation) than in patients with smaller lacunar infarcts [92]. Further on, over 2000 SCAST patients were randomly allocated to placebo or CS treatment for seven days with increasing doses from 4 mg (starting day 1) to 16 mg (from day 3 to 7). After six months’ follow-up, the risk of the composite vascular endpoint did not differ between the placebo and CS treatment group [93]. Also, the Acute Candesartan Cilexetil Therapy in Stroke Survivors study confirmed that administration of CS in the acute phase of stroke in 339 patients confers long-term benefits in patients who sustained acute ischemic stroke [94]. VS has been evaluated in a multicenter trial concerning efficacy and safety of modest blood pressure reduction within 48 h in more than 370 patients with acute ischemic stroke, considering the primary outcome death or dependency. The VS-treated group showed 46 of 187 patients with a 90-day mRS of 3–6, compared with 42 of 185 patients in the control group. The rate of major vascular events did not differ significantly between both groups [98]. TMS has also been evaluated concerning beneficial effects after stroke treatment. A multicenter trial, involving more than 18,500 patients with ischemic stroke, had a follow-up of 2.5 years. The primary outcome parameter was time to first recurrent stroke. Only short-term add-on TMS (80 mg/day) treatment did not mitigate this risk [100,101]. Treatment with TMS (80 mg/day) did not prevent progression of white matter lesions in patients with recent ischemic stroke [102]. Another study group enrolled 20,332 patients and analyzed 1360 patients within 72 h of ischemic stroke onset (TMS vs. placebo) concerning functional outcome after 30 days as primary outcome. Combined death or dependency did not differ between the treatment groups, showing treatment with TMS (80 mg/day) in patients with acute mild ischemic stroke and mildly elevated BP safe with no excess in adverse events [103]. Also, effects of TMS (80 mg/day) initiation early after stroke have been analyzed. From 20,332 patients with recent ischemic stroke, 10,146 patients were randomly assigned in the TMS group and 10,186 in the placebo group; 8.7% in the TMS group and 9.2% in the placebo group suffered from subsequent stroke, showing no significant reduction of recurrent stroke after early initiation [104]. LS has also been analyzed in recent clinical stroke trials. In a double-blinded multi-center trial, 196 hypertensive patients with previous ischemic stroke were randomized to cilnidipine- or LS-treatment (50–100 mg per day for four weeks) once daily for four weeks. Both treatments, however, increased global CBF despite BP lowering [105]. Additionally, the effect of long-term therapy with LS regarding cognitive function in 6206 essential hypertonic patients with additional cerebrovascular risk factors was investigated. The LS-based antihypertensive treatment increased the proportion of patients with normal cognitive function [109]. Also, the Losartan Intervention for Endpoint reduction in hypertension study group reported cardioprotective effects of a LS-based antihypertensive regimen. The incidence of any stroke, fatal stroke, and atherothrombotic stroke was significantly lower in LS-treated compared to the atenolol-treated isolated systolic hypertensive patients [106]. Other groups assessed the effect of LS treatment on mean arterial blood pressure, global, and focal CBF in 24 hypertensive patients without occlusive carotid disease 2–7 days after ischemic stroke and/or transient ischemic attack. LS (25–50 mg per day) was generally well tolerated and none of the patients suffered neurological deterioration. No changes occurred in internal carotid artery flow or cortical as well as hemispheric CBF [107].

3.3. Therapeutic Interventions After aSAH Poor patients’ outcome after aSAH is owed a multifactorial process (early brain injury, DCVS, DCI, cerebral inflammation, cortical spreading depression, loss of pressure dependent cerebral autoregulation) [4,5,7,9,110–113]. DCVS is treated with moderate hypertensive, normovolemic, Brain Sci. 2020, 10, 153 14 of 25 hemodilution, and in cases of therapy-refractory, DCVS with intra-arterial spasmolysis or balloon dilatation [114,115]. Research to improve poor functional outcome in patients suffering from aSAH and related DCVS is pivotal [1,5,21,116,117]. Multiple preclinical and clinical trials showed the effect of ET-1 in mediating DCVS after aSAH. CONSCIOUS-1, a randomized, double-blind, placebo-controlled study assessed the efficacy of intravenous clazosentan (ETA-R antagonist) in preventing vasospasm following aSAH. It significantly decreased angiographic DCVS with a trend for reduction in vasospasm-related morbidity/mortality [118]. CONSCIOUS-2 assigned patients with aSAH and clip ligation to clazosentan- or placebo. Thereby, clazosentan showed no significant difference in the mortality and vasospasm-related morbidity [119]. CONSCIOUS-3 assessed whether clazosentan reduced DCVS-related morbidity and mortality after aSAH and endovascular coiling. Pulmonary complications and were more common in patients with clazosentan administration than in the placebo group, and mortality rates after 12 weeks were the same, respectively [120]. The REVERSE-study, infusing clazosentan intravenously in patients developing moderate to severe angiographic vasospasm after aSAH, showed a clear pharmacodynamic dilating effect on DCVS 24 h in most patients suffering aSAH, being able to reverse established angiographic vasospasm [22]. Antihypertensive agents are usually discontinued to maintain a sufficient mean arterial cerebral perfusion pressure considering the prolonged phase of DCVS between days 5 to 14 after the ictus [114]. In contrast, nimodipine, a -channel antagonist, is administered for risk reduction of DCVS, yet rather its neuroprotective effects have been discussed in its beneficial role in aSAH [8,121].

3.4. Effects of Losartan Following aSAH LS, an already well-established antihypertensive drug in daily clinical practice and well examined in preclinical and clinical settings of ischemic stroke, shows promising results by attenuating cerebral inflammation and restoring cerebral autoregulation [64,105,122–125]. Facing preclinical aSAH research, beneficial effects of Sartans have been shown. Under already physiological conditions, LS diminished cerebral inflammation and associated DCVS [126] as well as ET-1 mediated vasoconstriction. Targeted ETB1- and ETA-R-antagonism under LS administration revealed a direct modulatory ETB1-R dependent effect via inducing upregulation of the NO-pathway with a significantly increased relaxation accompanied with enhanced sensitivity of the ETB1-R [23]. After induction of aSAH, ET-1-induced vasoconstriction was likewise decreased by LS preincubation, abolished after pretreatment with an ETB1-R antagonist. In precontracted vessels with LS and ETA-R-antagonism, ET-1 induced a higher vasorelaxation compared to the control group without, clearly demonstrating a modulatory and functional restoring effect of LS on the normally after aSAH impaired ETB1-R function [127]. Beneficial effects of LS on ET-1- and PGF2α-mediated DCVS after aSAH in a rat model have been reported, too [23,127]. An ET-1 mediated vasoconstriction was diminished, and ETB1-R mediated vasorelaxation under selective ETA-R blockade was restored [126,127]. In addition, PGF2α-elicited vasoconstriction of a basilar artery was markedly diminished [23,126,127]. Interestingly, several work groups could also verify positive vasomodulating effects of LS on the cerebral vessel wall, especially affecting SMCs [128,129]. Furthermore, rupture was prevented in mice under LS treatment [129]. As already mentioned, after aSAH, increased synthesis of ET-1 triggers enhanced cerebral vasoconstriction; loss of the ETB1-R mediated vasorelaxation contributes to this effect, too [127]. Furthermore, upregulated AT2-1-R and PGF2α-synthesis contribute in enhancing and maintaining cerebral vasocontraction [7,130–133]. LS showed promising aspects in preclinical aSAH studies and therefore might have an effect in the treatment of patients with aSAH.

4. Discussions This systematic review demonstrated Sartan administration after ischemic stroke clearly associated with beneficial effects on preclinical models as well regarding clinical trials. Clear evidence of which doses in preclinical and clinical settings for treatment of ischemic stroke with Sartans exactly might be useful are heterogenous and therefore not consistent yet. In a preclinical setting, Sartans significantly Brain Sci. 2020, 10, 153 15 of 25 reduced infarct volume and edema, augmented CBF, diminished superoxide production, inflammatory processes, and disruption of the BBB. In clinical studies, clear trends towards a better functional outcome and neurocognitive function after stroke with Sartan use have been reported. Thus, the question arises whether Sartans might provide positive effects on DCVS or DCI after aSAH. In summary, LS provided in a preclinical physiological and pathophysiological setup after aSAH beneficial aspects in reducing ET-1- and PGF2α mediated cerebral vasoconstriction [126,130]. Vasoconstriction was notably reduced and the vasorelaxant properties of the ETB1-R were restored. Furthermore, clear evidence exists, that after aSAH, AT2-1-R are upregulated in experimental settings [132]. Here, an additive direct antagonism on these receptors could reduce the sensitivity to an AT2-1-R-mediated vasocontraction to angiotensin II, too [125,134]. LS possesses beneficial aspects on cerebral epileptogenicity, which could be applied to the issue of reducing cortical spreading depression post aSAH [135–138]. Also, it is able to restore post-ischemic cerebral autoregulation after hemorrhagic stroke [134]. Considering these neuroprotective effects of LS, the ethical question arises of whether the philosophy of strictly discontinuing all antihypertensive agents after aSAH (except of new administration of nimodipine), especially of LS, should stay state of the art. Next to beneficial influences on DCVS after aSAH in rats as mentioned above, AT2-1-R antagonists clearly possess beneficial effects after stroke regarding cerebral inflammation, the areal of infarction, cortical spreading depression, cerebral microcirculation, and maintenance of pressure-dependent cerebral vasoconstriction [23,64,71,105,127,134,139–141]. Appreciating these facts, a systemic LS administration over and above the phase of DCVS, could be a promising approach in preventing these effects; particularly because LS seems to not influence the global CBF in essential hypertonic patients, which can be set equivalent to a needed-hypertonia after aSAH [142]. Here, LS could be an interesting approach, because it increases global CBF despite lowering blood pressure [105], and is therefore capable to reduce DCI [92]. Also, considering the positive vasomodulatory influences of LS, the question arises whether after aSAH this medication should be established as secondary prophylaxis to avoid a de-novo-aneurysm genesis, ergo, if under LS are anyway arising [143].

4.1. Translational Aspects Both abovementioned questions after aSAH are difficult to adapt to the affected patient group, because common sense to date stays in discontinuing all antihypertensive agents after the initial bleeding event. Also, it is vague to postulate that a LS effect persists after discharging this medication on admission over the phase of DCVS for 14 days. Furthermore, the numbers of patients with LS as standard antihypertonic medication receiving follow-up angiographys are too scarce to testify a valid statement concerning case-control studies of aneurysm-growth/-development, as reviewed in our own patient series in 2009–2015. Nevertheless, LS seems to be an underrated neuroprotective drug, reducing cerebral inflammation and epileptogenicity, DCVS, and infarct size after ischemic stroke. These results of preclinical ischemic stroke and aSAH research as well as clinical ischemic stroke research could be applied in a prospective clinical setting of patients suffering aSAH. Also, the question of a de-novo-aneurysm-genesis in further cranial control imaging could be addressed.

4.2. Synopsis and Forecast

LS, a selective AT2-1-R antagonist, was shown to directly antagonize and ameliorate the impaired ETB1-R vasodilatory function. Given that in most clinical centers, antihypertensive agents are discontinued during the period of DCVS, LS, although an antihypertensive drug, may have a role in preventing delayed DCVS after aneurysm rupture given the effects shown in ischemia. Following aSAH, immediate therapy with LS might antagonize the vasoconstrictive AT2-1-R without affecting the dilatory AT2-2-R effect [132,144–151]. Furthermore, AT2 interestingly increases endothelin production in non-cerebral vessels (an increased ET-1 concentration in rat aortas could be inhibited through LS administration [140]) and thus indirectly enhances ET-1-mediated DCVS [123,152–156]. All these aspects might suggest a crosstalk between both peptidergic systems extra- and intracranially [71,157]. Brain Sci. 2020, 10, 153 16 of 25

5. Conclusions There is a promising effect on LS in the treatment of ischemic stroke both in preclinical and clinical studies as well as in preclinical studies on aSAH. LS has shown to reduce ET-1-mediated vasocontraction, cerebral inflammation, and restores vasodilatory function of the ETB1-R [26–28]. Thus, LS may decrease the incidence of symptomatic vasospasm and improve functional outcome in aSAH patients. Large, randomized, double-blinded clinical trials are necessary to determine its benefit in aSAH.

Author Contributions: S.W. and L.A.: Design of the review, collection and analysis of data, drafting the manuscript; B.E.G., S.D.S., H.R.W., S.M., and J.F.: Critical revision of the first draft; All of the authors: Critical revision of the final manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Vatter, H.; Konczalla, J.; Weidauer, S.; Preibisch, C.; Zimmermann, M.; Raabe, A.; Seifert, V. Effect of delayed cerebral vasospasm on cerebrovascular endothelin A receptor expression and function. J. Neurosurg. 2007, 107, 121–127. [CrossRef] 2. Brandt, L.; Ljunggren, B.; Andersson, K.E.; Hindfelt, B.; Uski, T. Prostaglandin metabolism and prostacyclin in cerebral vasospasm. Gen. Pharmacol. 1983, 14, 141–143. [CrossRef] 3. Egg, D.; Herold, M.; Rumpl, E.; Gunther, R. Prostaglandin F2 alpha levels in human cerebrospinal fluid in normal and pathological conditions. J. Neurol. 1980, 222, 239–248. [CrossRef][PubMed] 4. Fujii, M.; Yan, J.; Rolland, W.B.; Soejima, Y.; Caner, B.; Zhang, J.H. Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Transl. Stroke Res. 2013, 4, 432–446. [CrossRef][PubMed] 5. Dreier, J.P.; Drenckhahn, C.; Woitzik, J.; Major, S.; Offenhauser, N.; Weber-Carstens, S.; Wolf, S.; Strong, A.J.; Vajkoczy, P.; Hartings, J.A.; et al. Spreading ischemia after aneurysmal subarachnoid hemorrhage. Acta Neurochir. Suppl. 2013, 115, 125–129. [PubMed] 6. Vergouwen, M.D.; Vermeulen, M.; van Gijn, J.; Rinkel, G.J.; Wijdicks, E.F.; Muizelaar, J.P.; Mendelow, A.D.; Juvela, S.; Yonas, H.; Terbrugge, K.G.; et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: Proposal of a multidisciplinary research group. Stroke 2010, 41, 2391–2395. [CrossRef][PubMed] 7. Budohoski, K.P.; Czosnyka, M.; Smielewski, P.; Kasprowicz, M.; Helmy, A.; Bulters, D.; Pickard, J.D.; Kirkpatrick, P.J. Impairment of cerebral autoregulation predicts delayed cerebral ischemia after subarachnoid hemorrhage: A prospective observational study. Stroke 2012, 43, 3230–3237. [CrossRef] 8. Bederson, J.B.; Connolly, E.S.; Batjer, H.H., Jr.; Dacey, R.G.; Dion, J.E.; Diringer, M.N.; Duldner, J.E., Jr.; Harbaugh, R.E.; Patel, A.B.; Rosenwasser, R.H.; et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 2009, 40, 994–1025. [CrossRef] 9. Salom, J.B.; Torregrosa, G.; Alborch, E. Endothelins and the cerebral circulation. Cerebrovasc. Brain Metab. Rev. 1995, 7, 131–152. 10. Vatter, H.; Zimmermann, M.; Seifert, V.; Schilling, L. Experimental approaches to evaluate endothelin-A receptor antagonists. Methods Find. Exp. Clin. Pharmacol. 2004, 26, 277–286. 11. Zimmermann, M.; Seifert, V. Endothelin and subarachnoid hemorrhage: An overview. Neurosurgery 1998, 43, 863–875. [CrossRef][PubMed] 12. Neuschmelting, V.; Marbacher, S.; Fathi, A.R.; Jakob, S.M.; Fandino, J. Elevated level of endothelin-1 in cerebrospinal fluid and lack of nitric oxide in basilar arterial plasma associated with cerebral vasospasm after subarachnoid haemorrhage in rabbits. Acta Neurochir. 2009, 151, 795–801. [CrossRef][PubMed] 13. Josko, J.; Hendryk, S.; Jedrzejowska-Szypulka, H.; Slowinski, J.; Gwozdz, B.; Lange, D.; Harabin-Slowinska, M. Effect of endothelin-1 receptor antagonist BQ-123 on basilar artery diameter after subarachnoid hemorrhage (SAH) in rats. J. Physiol. Pharmacol. 2000, 51, 241–249. [PubMed] Brain Sci. 2020, 10, 153 17 of 25

14. Nishizawa, S.; Chen, D.; Yokoyama, T.; Yokota, N.; Otha, S. Endothelin-1 initiates the development of vasospasm after subarachnoid haemorrhage through protein kinase C activation, but does not contribute to prolonged vasospasm. Acta Neurochir. 2000, 142, 1409–1415. [CrossRef][PubMed] 15. Hansen-Schwartz, J.; Hoel, N.L.; Zhou, M.; Xu, C.B.; Svendgaard, N.A.; Edvinsson, L. Subarachnoid hemorrhage enhances endothelin receptor expression and function in rat cerebral arteries. Neurosurgery 2003, 52, 1188–1194. [PubMed] 16. Lei, Q.; Li, S.; Zheng, R.; Xu, K.; Li, S. Endothelin-1 expression and alterations of cerebral microcirculation after experimental subarachnoid hemorrhage. Neuroradiology 2015, 57, 63–70. [CrossRef][PubMed] 17. Josko, J.; Hendryk, S.; Jedrzejowska-Szypulka, H.; Slowinski, J.; Gwozdz, B.; Lange, D.; Snietura, M.; Zwirska-Korczala, K.; Jochem, J. Cerebral angiogenesis after subarachnoid hemorrhage (SAH) and endothelin receptor blockage with BQ-123 antagonist in rats. J. Physiol. Pharmacol. 2001, 52, 237–248. 18. Xie, A.; Aihara, Y.; Bouryi, V.A.; Nikitina, E.; Jahromi, B.S.; Zhang, Z.D.; Takahashi, M.; Macdonald, R.L. Novel mechanism of endothelin-1-induced vasospasm after subarachnoid hemorrhage. J. Cereb. Blood Flow Metab. 2007, 27, 1692–1701. [CrossRef] 19. Kim, C.Y.; Paek, S.H.; Seo, B.G.; Kim, J.H.; Han, D.H. Changes in vascular responses of the basilar artery to acetylcholine and endothelin-1 in an experimental rabbit vasospasm model. Acta Neurochir. 2003, 145, 571–577. [CrossRef] 20. Chow, M.; Dumont, A.S.; Kassell, N.F. Endothelin receptor antagonists and cerebral vasospasm: An update. Neurosurgery 2002, 51, 1333–1341. [CrossRef] 21. Macdonald, R.L.; Higashida, R.T.; Keller, E.; Mayer, S.A.; Molyneux, A.; Raabe, A.; Vajkoczy, P.; Wanke, I.; Bach, D.; Frey, A.; et al. Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2). Acta Neurochir. Suppl. 2013, 115, 27–31. [PubMed] 22. Higashida, R.T.; Bruder, N.; Gupta, R.; Guzman, R.; Hmissi, A.; Marr, A.; Mayer, S.A.; Roux, S.; Weidauer, S.; Aldrich, E.F. Reversal of Vasospasm with Clazosentan After Aneurysmal Subarachnoid Hemorrhage: A Pilot Study. World Neurosurg. 2019, 128, e639–e648. [CrossRef][PubMed] 23. Konczalla, J.; Wanderer, S.; Mrosek, J.; Schuss, P.; Platz, J.; Güresir, E.; Seifert, V.; Vatter, H. Crosstalk between the angiotensin and endothelin-system in the cerebrovasculature. Curr. Neurovasc. Res. 2013, 10, 335–345. [CrossRef][PubMed] 24. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; Group, P. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [CrossRef] 25. Justin, A.; Divakar, S.; Ramanathan, M. Cerebral ischemia induced inflammatory response and altered glutaminergic function mediated through brain AT1 and not AT2 receptor. Biomed. Pharmacother. 2018, 102, 947–958. [CrossRef] 26. Iwanami, J.; Mogi, M.; Tsukuda, K.; Min, L.J.; Sakata, A.; Jing, F.; Iwai, M.; Horiuchi, M. Low dose of telmisartan prevents ischemic brain damage with peroxisome proliferator-activated receptor-gamma activation in diabetic mice. J. Hypertens. 2010, 28, 1730–1737. [CrossRef] 27. Kasahara, Y.; Taguchi, A.; Uno, H.; Nakano, A.; Nakagomi, T.; Hirose, H.; Stern, D.M.; Matsuyama, T. Telmisartan suppresses cerebral injury in a murine model of transient focal ischemia. Brain Res. 2010, 1340, 70–80. [CrossRef] 28. Iwai, M.; Inaba, S.; Tomono, Y.; Kanno, H.; Iwanami, J.; Mogi, M.; Horiuchi, M. Attenuation of focal brain ischemia by telmisartan, an angiotensin II type 1 receptor blocker, in atherosclerotic apolipoprotein E-deficient mice. Hypertens. Res. 2008, 31, 161–168. [CrossRef] 29. Li, T.; Zhang, Y.; Zhu, B.; Wu, C.; Chen, Y. Telmisartan regulates the development of cerebral ischemia by alleviating endoplasmic reticulum stress. Pharmazie 2018, 73, 585–588. 30. Gao, Y.; Li, W.; Liu, Y.; Wang, Y.; Zhang, J.; Li, M.; Bu, M. Effect of Telmisartan on Preventing Learning and Memory Deficits Via Peroxisome Proliferator-Activated Receptor-gamma in Spontaneously Hypertensive Rats. J. Stroke Cerebrovasc. Dis. 2018, 27, 277–285. [CrossRef] 31. Ramanathan, M.; Justin, A.; Sudheer, A.; Shanthakumari, S. Comparison of pre- and post-ischemic treatment of telmisartan and nimodipine combination in experimentally induced cerebral ischemia. Indian J. Exp. Biol. 2016, 54, 560–568. Brain Sci. 2020, 10, 153 18 of 25

32. Kono, S.; Kurata, T.; Sato, K.; Omote, Y.; Hishikawa, N.; Yamashita, T.; Deguchi, K.; Abe, K. Neurovascular protection by telmisartan via reducing neuroinflammation in stroke-resistant spontaneously hypertensive rat brain after ischemic stroke. J. Stroke Cerebrovasc. Dis. 2015, 24, 537–547. [CrossRef][PubMed] 33. Dupuis, F.; Vincent, J.M.; Liminana, P.; Chillon, J.M.; Capdeville-Atkinson, C.; Atkinson, J. Effects of suboptimal doses of the AT1 receptor blocker, telmisartan, with the angiotensin-converting enzyme inhibitor, ramipril, on cerebral arterioles in spontaneously hypertensive rat. J. Hypertens. 2010, 28, 1566–1573. [CrossRef][PubMed] 34. Deguchi, K.; Kurata, T.; Fukui, Y.; Liu, W.; Yun, Z.; Omote, Y.; Sato, K.; Kono, S.; Hishikawa, N.; Yamashita, T.; et al. Long-term amelioration of telmisartan on metabolic syndrome-related molecules in stroke-resistant spontaneously hypertensive rat after transient middle cerebral artery occlusion. J. Stroke Cerebrovasc. Dis. 2014, 23, 2646–2653. [CrossRef] 35. Thoene-Reineke, C.; Rumschussel, K.; Schmerbach, K.; Krikov, M.; Wengenmayer, C.; Godes, M.; Mueller, S.; Villringer, A.; Steckelings, U.; Namsolleck, P.; et al. Prevention and intervention studies with telmisartan, ramipril and their combination in different rat stroke models. PLoS ONE 2011, 6, e23646. [CrossRef] 36. Kobayashi, T.; Kawamata, T.; Shibata, N.; Okada, Y.; Kobayashi, M.; Hori, T. Angiotensin II type 1 receptor blocker telmisartan reduces cerebral infarct volume and peri-infarct cytosolic phospholipase A(2) level in experimental stroke. J. Neurotrauma. 2009, 26, 2355–2364. [CrossRef] 37. Jung, K.H.; Chu, K.; Lee, S.T.; Kim, S.J.; Song, E.C.; Kim, E.H.; Park, D.K.; Sinn, D.I.; Kim, J.M.; Kim, M. Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with . J. Pharmacol. Exp. Ther. 2007, 322, 1051–1058. [CrossRef] 38. Fukui, Y.; Yamashita, T.; Kurata, T.; Sato, K.; Lukic, V.; Hishikawa, N.; Deguchi, K.; Abe, K. Protective effect of telmisartan against progressive oxidative brain damage and synuclein phosphorylation in stroke-resistant spontaneously hypertensive rats. J. Stroke Cerebrovasc. Dis. 2014, 23, 1545–1553. [CrossRef] 39. Hamai, M.; Iwai, M.; Ide, A.; Tomochika, H.; Tomono, Y.; Mogi, M.; Horiuchi, M. Comparison of inhibitory action of candesartan and enalapril on brain ischemia through inhibition of oxidative stress. Neuropharmacology 2006, 51, 822–828. [CrossRef] 40. Awad, A.S. Effect of combined treatment with curcumin and candesartan on ischemic brain damage in mice. J. Stroke Cerebrovasc. Dis. 2011, 20, 541–548. [CrossRef] 41. Soliman, S.; Ishrat, T.; Fouda, A.Y.; Patel, A.; Pillai, B.; Fagan, S.C. Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke. Transl. Stroke Res. 2015, 6, 309–322. [CrossRef][PubMed] 42. Ishrat, T.; Soliman, S.; Eldahshan, W.; Pillai, B.; Ergul, A.; Fagan, S.C. Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia. Neurochem. Res. 2018, 43, 1869–1878. [CrossRef][PubMed] 43. Culman, J.; Jacob, T.; Schuster, S.O.; Brolund-Spaether, K.; Brolund, L.; Cascorbi, I.; Zhao, Y.; Gohlke, P. Neuroprotective effects of AT1 receptor antagonists after experimental ischemic stroke: What is important? Naunyn. Schmiedebergs Arch. Pharmacol. 2017, 390, 949–959. [CrossRef][PubMed] 44. Alhusban, A.; Kozak, A.; Pillai, B.; Ahmed, H.; Sayed, M.A.; Johnson, M.H.; Ishrat, T.; Ergul, A.; Fagan, S.C. Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension. PLoS ONE 2017, 12, e0178867. [CrossRef] 45. Fouda, A.Y.; Alhusban, A.; Ishrat, T.; Pillai, B.; Eldahshan, W.; Waller, J.L.; Ergul, A.; Fagan, S.C. Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke. Mol. Neurobiol. 2017, 54, 661–670. [CrossRef] 46. Soliman, S.; Ishrat, T.; Pillai, A.; Somanath, P.R.; Ergul, A.; El-Remessy, A.B.; Fagan, S.C. Candesartan induces a prolonged proangiogenic effect and augments endothelium-mediated neuroprotection after oxygen and glucose deprivation: Role of vascular endothelial growth factors A and B. J. Pharmacol. Exp. Ther. 2014, 349, 444–457. [CrossRef] 47. Alhusban, A.; Kozak, A.; Ergul, A.; Fagan, S.C. AT1 receptor antagonism is proangiogenic in the brain: BDNF a novel mediator. J. Pharmacol. Exp. Ther. 2013, 344, 348–359. [CrossRef] 48. So, G.; Nakagawa, S.; Morofuji, Y.; Hiu, T.; Hayashi, K.; Tanaka, K.; Suyama, K.; Deli, M.A.; Nagata, I.; Matsuo, T.; et al. Candesartan improves ischemia-induced impairment of the blood-brain barrier in vitro. Cell Mol. Neurobiol. 2015, 35, 563–572. [CrossRef] Brain Sci. 2020, 10, 153 19 of 25

49. Panahpour, H.; Nekooeian, A.A.; Dehghani, G.A. Candesartan attenuates ischemic brain edema and protects the blood-brain barrier integrity from ischemia/reperfusion injury in rats. Iran. Biomed. J. 2014, 18, 232–238. 50. Ishrat, T.; Pillai, B.; Soliman, S.; Fouda, A.Y.; Kozak, A.; Johnson, M.H.; Ergul, A.; Fagan, S.C. Low-dose candesartan enhances molecular mediators of neuroplasticity and subsequent functional recovery after ischemic stroke in rats. Mol. Neurobiol. 2015, 51, 1542–1553. [CrossRef] 51. Guan, W.; Kozak, A.; Fagan, S.C. Drug repurposing for vascular protection after acute ischemic stroke. Acta Neurochir. Suppl. 2011, 111, 295–298. [PubMed] 52. Schmerbach, K.; Pfab, T.; Zhao, Y.; Culman, J.; Mueller, S.; Villringer, A.; Muller, D.N.; Hocher, B.; Unger, T.; Thoene-Reineke, C. Effects of aliskiren on stroke in rats expressing human renin and angiotensinogen genes. PLoS ONE 2010, 5, e15052. [CrossRef][PubMed] 53. Omura-Matsuoka, E.; Yagita, Y.; Sasaki, T.; Terasaki, Y.; Oyama, N.; Sugiyama, Y.; Okazaki, S.; Ssakoda, S.; Kitagawa, K. Postischemic administration of angiotensin II type 1 receptor blocker reduces size in hypertensive rats. Hypertens. Res. 2009, 32, 548–553. [CrossRef] 54. Kozak, W.; Kozak, A.; Johnson, M.H.; Elewa, H.F.; Fagan, S.C. Vascular protection with candesartan after experimental acute stroke in hypertensive rats: A dose-response study. J. Pharmacol. Exp. Ther. 2008, 326, 773–782. [CrossRef][PubMed] 55. Krikov, M.; Thone-Reineke, C.; Muller, S.; Villringer, A.; Unger, T. Candesartan but not ramipril pretreatment improves outcome after stroke and stimulates neurotrophin BNDF/TrkB system in rats. J. Hypertens. 2008, 26, 544–552. [CrossRef][PubMed] 56. Fagan, S.C.; Kozak, A.; Hill, W.D.; Pollock, D.M.; Xu, L.; Johnson, M.H.; Ergul, A.; Hess, D.C. Hypertension after experimental cerebral ischemia: Candesartan provides neurovascular protection. J. Hypertens. 2006, 24, 535–539. [CrossRef][PubMed] 57. Lu, Q.; Zhu, Y.Z.; Wong, P.T. Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats. Neuroreport 2005, 16, 1963–1967. [CrossRef] 58. Kusaka, I.; Kusaka, G.; Zhou, C.; Ishikawa, M.; Nanda, A.; Granger, D.N.; Zhang, J.H.; Tang, J. Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. Am. J. Physiol. Heart Circ. Physiol. 2004, 286, H2442–H2451. [CrossRef] 59. Groth, W.; Blume, A.; Gohlke, P.; Unger, T.; Culman, J. Chronic pretreatment with candesartan improves recovery from focal cerebral ischaemia in rats. J. Hypertens. 2003, 21, 2175–2182. [CrossRef] 60. Nishimura, Y.; Ito, T.; Saavedra, J.M. Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 2000, 31, 2478–2486. [CrossRef] 61. Gaur, V.; Kumar, A. Neuroprotective potentials of candesartan, atorvastatin and their combination against stroke induced motor dysfunction. Inflammopharmacology 2011, 19, 205–214. [CrossRef][PubMed] 62. Engelhorn, T.; Doerfler, A.; Heusch, G.; Schulz, R. Reduction of cerebral infarct size by the AT1-receptor blocker candesartan, the HMG-CoA reductase inhibitor rosuvastatin and their combination. An experimental study in rats. Neurosci. Lett. 2006, 406, 92–96. [CrossRef][PubMed] 63. Mecca, A.P.; O’Connor, T.E.; Katovich, M.J.; Sumners, C. Candesartan pretreatment is cerebroprotective in a rat model of endothelin-1-induced middle cerebral artery occlusion. Exp. Physiol. 2009, 94, 937–946. [CrossRef][PubMed] 64. Schmerbach, K.; Schefe, J.H.; Krikov, M.; Müller, S.; Villringer, A.; Kintscher, U.; Unger, T.; Thoene-Reineke, C. Comparison between single and combined treatment with candesartan and pioglitazone following transient focal ischemia in rat brain. Brain Res. 2008, 1208, 225–233. [CrossRef][PubMed] 65. Zhou, J.; Pavel, J.; Macova, M.; Yu, Z.X.; Imboden, H.; Ge, L.; Nishioku, T.; Dou, J.; Delgiacco, E.; Saavedra, J.M. AT1 receptor blockade regulates the local angiotensin II system in cerebral microvessels from spontaneously hypertensive rats. Stroke 2006, 37, 1271–1276. [CrossRef][PubMed] 66. Kozak, A.; Ergul, A.; El-Remessy, A.B.; Johnson, M.H.; Machado, L.S.; Elewa, H.F.; Abdelsaid, M.; Wiley, D.C.; Fagan, S.C. Candesartan augments ischemia-induced proangiogenic state and results in sustained improvement after stroke. Stroke 2009, 40, 1870–1876. [CrossRef][PubMed] 67. Faure, S.; Bureau, A.; Oudart, N.; Javellaud, J.; Fournier, A.; Achard, J.M. Protective effect of candesartan in experimental ischemic stroke in the rat mediated by AT2 and AT4 receptors. J. Hypertens. 2008, 26, 2008–2015. [CrossRef] Brain Sci. 2020, 10, 153 20 of 25

68. Stenman, E.; Jamali, R.; Henriksson, M.; Maddahi, A.; Edvinsson, L. Cooperative effect of angiotensin AT(1) and endothelin ET(A) receptor antagonism limits the brain damage after ischemic stroke in rat. Eur. J. Pharmacol. 2007, 570, 142–148. [CrossRef] 69. Stenman, E.; Edvinsson, L. Cerebral ischemia enhances vascular angiotensin AT1 receptor-mediated contraction in rats. Stroke 2004, 35, 970–974. [CrossRef] 70. Brdon, J.; Kaiser, S.; Hagemann, F.; Zhao, Y.; Culman, J.; Gohlke, P. Comparison between early and delayed systemic treatment with candesartan of rats after ischaemic stroke. J. Hypertens. 2007, 25, 187–196. [CrossRef] [PubMed] 71. Engelhorn, T.; Goerike, S.; Doerfler, A.; Okorn, C.; Forsting, M.; Heusch, G.; Schulz, R. The angiotensin II type 1-receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 2004, 24, 467–474. [CrossRef] [PubMed] 72. Yamakawa, H.; Jezova, M.; Ando, H.; Saavedra, J.M. Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J. Cereb. Blood Flow Metab. 2003, 23, 371–380. [CrossRef][PubMed] 73. Nakagawa, T.; Hasegawa, Y.; Uekawa, K.; Senju, S.; Nakagata, N.; Matsui, K.; Kim-Mitsuyama, S. Transient Mild Cerebral Ischemia Significantly Deteriorated Cognitive Impairment in a Mouse Model of Alzheimer’s Disease via Angiotensin AT1 Receptor. Am. J. Hypertens. 2017, 30, 141–150. [CrossRef][PubMed] 74. Faure, S.; Oudart, N.; Javellaud, J.; Fournier, A.; Warnock, D.G.; Achard, J.M. Synergistic protective effects of erythropoietin and olmesartan on ischemic stroke survival and post-stroke memory dysfunctions in the gerbil. J. Hypertens. 2006, 24, 2255–2261. [CrossRef][PubMed] 75. Gutierrez-Fernandez, M.; Fuentes, B.; Rodriguez-Frutos, B.; Ramos-Cejudo, J.; Otero-Ortega, L.; Diez-Tejedor, E. Different protective and reparative effects of olmesartan in stroke according to time of administration and withdrawal. J. Neurosci. Res. 2015, 93, 806–814. [CrossRef][PubMed] 76. Oyama, N.; Yagita, Y.; Sasaki, T.; Omura-Matsuoka, E.; Terasaki, Y.; Sugiyama, Y.; Sakoda, S.; Kitagawa, K. An angiotensin II type 1 receptor blocker can preserve endothelial function and attenuate brain ischemic damage in spontaneously hypertensive rats. J. Neurosci. Res. 2010, 88, 2889–2898. [CrossRef] 77. Hosomi, N.; Nishiyama, A.; Ban, C.R.; Naya, T.; Takahashi, T.; Kohno, M.; Koziol, J.A. Angiotensin type 1 receptor blockage improves ischemic injury following transient focal cerebral ischemia. Neuroscience 2005, 134, 225–231. [CrossRef] 78. Li, J.M.; Mogi, M.; Iwanami, J.; Min, L.J.; Tsukuda, K.; Sakata, A.; Fujita, T.; Iwai, M.; Horiuchi, M. Temporary pretreatment with the angiotensin II type 1 receptor blocker, valsartan, prevents ischemic brain damage through an increase in capillary density. Stroke 2008, 39, 2029–2036. [CrossRef] 79. Miyamoto, N.; Zhang, N.; Tanaka, R.; Liu, M.; Hattori, N.; Urabe, T. Neuroprotective role of angiotensin II type 2 receptor after transient focal ischemia in mice brain. Neurosci. Res. 2008, 61, 249–256. [CrossRef] 80. Iwai, M.; Liu, H.W.; Chen, R.; Ide, A.; Okamoto, S.; Hata, R.; Sakanaka, M.; Shiuchi, T.; Horiuchi, M. Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor stimulation. Circulation 2004, 110, 843–848. [CrossRef] 81. Dong, Y.F.; Kataoka, K.; Tokutomi, Y.; Nako, H.; Nakamura, T.; Toyama, K.; Sueta, D.; Koibuchi, N.; Yamamoto, E.; Ogawa, H.; et al. Beneficial effects of combination of valsartan and amlodipine on salt-induced brain injury in hypertensive rats. J. Pharmacol. Exp. Ther. 2011, 339, 358–366. [CrossRef][PubMed] 82. Lou, M.; Blume, A.; Zhao, Y.; Gohlke, P.; Deuschl, G.; Herdegen, T.; Culman, J. Sustained blockade of brain AT1 receptors before and after focal cerebral ischemia alleviates neurologic deficits and reduces neuronal injury, apoptosis, and inflammatory responses in the rat. J. Cereb. Blood Flow Metab. 2004, 24, 536–547. [CrossRef][PubMed] 83. Dai, W.J.; Funk, A.; Herdegen, T.; Unger, T.; Culman, J. Blockade of central angiotensin AT(1) receptors improves neurological outcome and reduces expression of AP-1 transcription factors after focal brain ischemia in rats. Stroke 1999, 30, 2391–2398. [CrossRef] 84. Tsukuda, K.; Mogi, M.; Iwanami, J.; Min, L.J.; Jing, F.; Oshima, K.; Horiuchi, M. Irbesartan attenuates ischemic brain damage by inhibition of MCP-1/CCR2 signaling pathway beyond AT(1) receptor blockade. Biochem. Biophys. Res. Commun. 2011, 409, 275–279. [CrossRef] Brain Sci. 2020, 10, 153 21 of 25

85. Dalmay, F.; Mazouz, H.; Allard, J.; Pesteil, F.; Achard, J.M.; Fournier, A. Non-AT(1)-receptor-mediated protective effect of angiotensin against acute ischaemic stroke in the gerbil. J. Renin Angiotensin Aldosterone Syst. 2001, 2, 103–106. [CrossRef] 86. Chen, S.; Li, G.; Zhang, W.; Sigmund, C.D.; Olson, J.E.; Chen, Y. Ischemia-induced brain damage is enhanced in human renin and angiotensinogen double-transgenic mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009, 297, R1526–R1531. [CrossRef] 87. Loh, K.P.; Low, L.S.; Wong, W.H.; Zhou, S.; Huang, S.H.; De Silva, R.; Duan, W.; Chou, W.H.; Zhu, Y.Z. A comparison study of cerebral protection using Ginkgo biloba extract and Losartan on stroked rats. Neurosci. Lett. 2006, 398, 28–33. [CrossRef] 88. Forder, J.P.; Munzenmaier, D.H.; Greene, A.S. Angiogenic protection from focal ischemia with angiotensin II type 1 receptor blockade in the rat. Am. J. Physiol. Heart Circ. Physiol. 2005, 288, H1989–H1996. [CrossRef] 89. Miyamoto, N.; Tanaka, Y.; Ueno, Y.; Tanaka, R.; Hattori, N.; Urabe, T. Benefits of prestroke use of angiotensin type 1 receptor blockers on ischemic stroke severity. J. Stroke Cerebrovasc. Dis. 2012, 21, 363–368. [CrossRef] 90. Jusufovic, M.; Sandset, E.C.; Bath, P.M.; Berge, E.; Scandinavian Candesartan Acute Stroke Trial Study Group. Early blood pressure lowering treatment in acute stroke. Ordinal analysis of vascular events in the Scandinavian Candesartan Acute Stroke Trial (SCAST). J. Hypertens. 2016, 34, 1594–1598. [CrossRef] 91. Hornslien, A.G.; Sandset, E.C.; Wyller, T.B.; Berge, E.; Scandinavian Candesartan Acute Stroke Trial Study Group. Effects of candesartan in acute stroke on activities of daily living and level of care at 6 months. J. Hypertens. 2015, 33, 1487–1491. [CrossRef][PubMed] 92. Sandset, E.C.; Jusufovic, M.; Sandset, P.M.; Bath, P.M.; Berge, E.; Group, S.S. Effects of blood pressure-lowering treatment in different subtypes of acute ischemic stroke. Stroke 2015, 46, 877–879. [CrossRef][PubMed] 93. Sandset, E.C.; Bath, P.M.; Boysen, G.; Jatuzis, D.; Korv, J.; Lüders, S.; Murray, G.D.; Richter, P.S.; Roine, R.O.; Terent, A.; et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): A randomised, placebo-controlled, double-blind trial. Lancet 2011, 377, 741–750. [CrossRef] 94. Schrader, J.; Luders, S.; Kulschewski, A.; Berger, J.; Zidek, W.; Treib, J.; Einhäupl, K.; Diener, H.C.; Dominiak, P.; Acute Candesartan Cilexetil Therapy in Stroke Survivors Study Group. The ACCESS Study: Evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke 2003, 34, 1699–1703. [CrossRef] 95. Nakamura, T.; Tsutsumi, Y.; Shimizu, Y.; Uchiyama, S. Renin-angiotensin system blockade safely reduces blood pressure in patients with minor ischemic stroke during the acute phase. J. Stroke Cerebrovasc. Dis. 2010, 19, 435–440. [CrossRef] 96. Hallevi, H.; Hazan-Halevy, I.; Paran, E. Modification of neutrophil adhesion to human endothelial cell line in acute ischemic stroke by dipyridamole and candesartan. Eur. J. Neurol. 2007, 14, 1002–1007. [CrossRef] 97. Jusufovic, M.; Sandset, E.C.; Bath, P.M.; Karlson, B.W.; Berge, E.; Scandinavian Candesartan Acute Stroke Trial Study Group. Effects of blood pressure lowering in patients with acute ischemic stroke and carotid artery stenosis. Int. J. Stroke 2015, 10, 354–359. [CrossRef] 98. Oh, M.S.; Yu, K.H.; Hong, K.S.; Kang, D.W.; Park, J.M.; Bae, H.J.; Koo, J.; Lee, J.; Lee, B.C.; Valsartan Efficacy oN modesT blood pressUre Reduction in acute ischemic stroke (VENTURE) study group. Modest blood pressure reduction with valsartan in acute ischemic stroke: A prospective, randomized, open-label, blinded-end-point trial. Int. J. Stroke 2015, 10, 745–751. [CrossRef] 99. Serebruany, V.L.; Malinin, A.I.; Lowry, D.R.; Sane, D.C.; Webb, R.L.; Gottlieb, S.O.; O’Connor, C.M.; Hennekens, C.H. Effects of valsartan and valeryl 4-hydroxy valsartan on human platelets: A possible additional mechanism for clinical benefits. J. Cardiovasc. Pharmacol. 2004, 43, 677–684. [CrossRef] 100. Ovbiagele, B.; Bath, P.M.; Cotton, D.; Sha, N.; Diener, H.C.; Investigators, P.R. Low glomerular filtration rate, recurrent stroke risk, and effect of renin-angiotensin system modulation. Stroke 2013, 44, 3223–3225. [CrossRef] 101. Wadiwala, M.F.; Kamal, A.K. What is better antiplatelet agent to prevent recurrent stroke? J. Pak. Med. Assoc. 2012, 62, 976–977. [PubMed] 102. Weber, R.; Weimar, C.; Blatchford, J.; Hermansson, K.; Wanke, I.; Möller-Hartmann, C.; Gizweksi, E.R.; Forsting, M.; Demchuck, A.M.; Sacco, R.L.; et al. Telmisartan on top of antihypertensive treatment does not prevent progression of cerebral white matter lesions in the prevention regimen for effectively avoiding second strokes (PRoFESS) MRI substudy. Stroke 2012, 43, 2336–2342. [CrossRef][PubMed] Brain Sci. 2020, 10, 153 22 of 25

103. Bath, P.M.; Martin, R.H.; Palesch, Y.; Cotton, D.; Yusuf, S.; Saccor, R.; Diener, H.C.; Toni, D.; Estol, C.; Roberts, R.; et al. Effect of telmisartan on functional outcome, recurrence, and blood pressure in patients with acute mild ischemic stroke: A PRoFESS subgroup analysis. Stroke 2009, 40, 3541–3546. [CrossRef][PubMed] 104. Yusuf, S.; Diener, H.C.; Sacco, R.L.; Cotton, D.; Ounpuu, S.; Lawton, W.A.; Palesch, Y.; Martin, R.H.; Albers, G.W.; Bath, P.; et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N. Engl. J. Med. 2008, 359, 1225–1237. [CrossRef] 105. Hong, K.S.; Kang, D.W.; Bae, H.J.; Kim, Y.K.; Han, M.K.; Park, J.M.; Rha, J.H.; Lee, Y.S.; Koo, J.S.; Cho, Y.J.; et al. Effect of cilnidipine vs. losartan on cerebral blood flow in hypertensive patients with a history of ischemic stroke: A randomized controlled trial. Acta Neurol. Scand. 2010, 121, 51–57. [CrossRef] 106. Kjeldsen, S.E.; Lyle, P.A.; Kizer, J.R.; Dahlhöf, B.; Devereux, R.B.; Julius, S.; Beevers, G.; de Faire, U.; Fyhrquist, F.; Ibsen, H.; et al. The effects of losartan compared to atenolol on stroke in patients with isolated systolic hypertension and left ventricular hypertrophy. The LIFE study. J. Clin. Hypertens. 2005, 7, 152–158. [CrossRef] 107. Nazir, F.S.; Overell, J.R.; Bolster, A.; Hilditch, T.E.; Reid, J.L.; Lees, K.R. The effect of losartan on global and focal cerebral perfusion and on renal function in hypertensives in mild early ischaemic stroke. J. Hypertens. 2004, 22, 989–995. [CrossRef] 108. Yamada, K.; Hirayama, T.; Hasegawa, Y. Antiplatelet effect of losartan and telmisartan in patients with ischemic stroke. J. Stroke Cerebrovasc. Dis. 2007, 16, 225–231. [CrossRef] 109. Van Ginneken, V.; Engel, P.; Fiebach, J.B.; Audebert, H.J.; Nolte, C.H.; Rocco, A. Prior antiplatelet therapy is not associated with larger hematoma volume or hematoma growth in intracerebral hemorrhage. Neurol. Sci. 2018, 39, 745–748. [CrossRef] 110. Vatter, H.; Konczalla, J.; Seifert, V. Endothelin related pathophysiology in cerebral vasospasm: What happens to the cerebral vessels? Acta Neurochir. Suppl. 2011, 110, 177–180. 111. Provencio, J.J. Inflammation in subarachnoid hemorrhage and delayed deterioration associated with vasospasm: A review. Acta Neurochir. Suppl. 2013, 115, 233–238. [PubMed] 112. Larysz-Brysz, M.; Lewin-Kowalik, J.; Czuba, Z.; Kotulska, K.; Olakowska, E.; Marcol, W.; Liskiewicz, A.; Jedrzejowska-Szypulka, H. Interleukin-1beta increases release of endothelin-1 and tumor necrosis factor as well as reactive oxygen species by peripheral leukocytes during experimental subarachnoid hemorrhage. Curr. Neurovasc. Res. 2012, 9, 159–166. [CrossRef][PubMed] 113. Paczkowska, E.; Golab-Janowska, M.; Bajer-Czajkowska, A.; Machalinska, A.; Ustianowski, P.; Rybicka, M.; Klos, P.; Dziedziejko, V.; Safranow, K.; Nowacki, P. Increased circulating endothelial progenitor cells in patients with haemorrhagic and ischaemic stroke: The role of endothelin-1. J. Neurol. Sci. 2013, 325, 90–99. [CrossRef][PubMed] 114. Andereggen, L.; Beck, J.; Z’Graggen, W.J.; Schroth, G.; Andres, R.H.; Murek, M.; Haenggi, M.; Reinert, M.; Raabe, A.; Gralla, J. Feasibility and Safety of Repeat Instant Endovascular Interventions in Patients with Refractory Cerebral . AJNR Am. J. Neuroradiol. 2017, 38, 561–567. [CrossRef] 115. Hosmann, A.; Rauscher, S.; Wang, W.T.; Dodier, P.; Bavinzski, G.; Knosp, E.; Gruber, A. Intra-Arterial Papaverine-Hydrochloride and Transluminal Balloon Angioplasty for Neurointerventional Management of Delayed-Onset Post-Aneurysmal Subarachnoid Hemorrhage Vasospasm. World Neurosurg. 2018, 119, e301–e312. [CrossRef] 116. Macdonald, R.L.; Higashida, R.T.; Keller, E.; Mayer, S.A.; Molyneux, A.; Raabe, A.; Vajkoczy, P.; Wanke, I.; Frey,A.; Marr, A.; et al. Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: Rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. Neurocrit. Care 2010, 13, 416–424. [CrossRef] 117. Raabe, A.; Beck, J.; Keller, M.; Vatter, H.; Zimmermann, M.; Seifert, V. Relative importance of hypertension compared with hypervolemia for increasing cerebral oxygenation in patients with cerebral vasospasm after subarachnoid hemorrhage. J. Neurosurg. 2005, 103, 974–981. [CrossRef] 118. Macdonald, R.L.; Kassell, N.F.; Mayer, S.; Ruefenacht, D.; Schmiedek, P.; Weidauer, S.; Frey, A.; Roux, S.; Pasqualin, A.; CONSCIOUS-1 Investigators. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): Randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 2008, 39, 3015–3021. [CrossRef] Brain Sci. 2020, 10, 153 23 of 25

119. Macdonald, R.L.; Higashida, R.T.; Keller, E.; Mayer, S.A.; Molyneux, A.; Raabe, A.; Vajkoczy, P.; Wanke, I.; Bach, D.; Frey, A.; et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: A randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011, 10, 618–625. [CrossRef] 120. Macdonald, R.L.; Higashida, R.T.; Keller, E.; Mayer, S.A.; Molyneux, A.; Raabe, A.; Vajkoczy, P.; Wanke, I.; Bach, D.; Frey, A.; et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 2012, 43, 1463–1469. [CrossRef] 121. Loch Macdonald, R. Management of cerebral vasospasm. Neurosurg. Rev. 2006, 29, 179–193. [CrossRef] [PubMed] 122. Rodrigues, S.F.; Granger, D.N. Cerebral microvascular inflammation in DOCA salt-induced hypertension: Role of angiotensin II and mitochondrial superoxide. J. Cereb. Blood Flow Metab. 2012, 32, 368–375. [CrossRef] [PubMed] 123. Zhang, R.; Witkowski, S.; Fu, Q.; Claassen, J.A.; Levine, B.D. Cerebral after short- and long-term reduction in blood pressure in mild and moderate hypertension. Hypertension 2007, 49, 1149–1155. [CrossRef][PubMed] 124. Andereggen, L.; Neuschmelting, V.; von Gunten, M.; Widmer, H.R.; Fandino, J.; Marbacher, S. The role of microclot formation in an acute subarachnoid hemorrhage model in the rabbit. Biomed. Res. Int. 2014, 2014, 161702. [CrossRef] 125. Bar-Klein, G.; Cacheaux, L.P.; Kamintsky, L.; Prager, O.; Weissberg, I.; Schoknecht, K.; Cheng, P.; Kim, S.Y.; Wood, L.; Heinemann, U.; et al. Losartan prevents acquired epilepsy via TGF-beta signaling suppression. Ann. Neurol. 2014, 75, 864–875. [CrossRef] 126. Wanderer, S.; Mrosek, J.; Gessler, F.; Seifert, V.; Konczalla, J. Vasomodulatory effects of the angiotensin II type 1 receptor antagonist losartan on experimentally induced cerebral vasospasm after subarachnoid haemorrhage. Acta Neurochir. 2018, 160, 277–284. [CrossRef] 127. Wanderer, S.; Mrosek, J.; Vatter, H.; Seifert, V.; Konczalla, J. Crosstalk between the angiotensin and endothelin system in the cerebrovasculature after experimental induced subarachnoid hemorrhage. Neurosurg. Rev. 2018, 41, 539–548. [CrossRef] 128. Gomez-Garre, D.; Martin-Ventura, J.L.; Granados, R.; Sancho, T.; Torres, R.; Ruano, M.; Garcia-Puig, J.; Egido, J. Losartan improves resistance artery lesions and prevents CTGF and TGF-beta production in mild hypertensive patients. Kidney Int. 2006, 69, 1237–1244. [CrossRef] 129. Tada, Y.; Wada, K.; Shimada, K.; Makino, H.; Liang, E.I.; Murakami, S.; Kudo, M.; Kitazato, K.T.; Nagahiro, S.; Hashimoto, T. Roles of hypertension in the rupture of intracranial aneurysms. Stroke 2014, 45, 579–586. [CrossRef] 130. Asaeda, M.; Sakamoto, M.; Kurosaki, M.; Tabuchi, S.; Kamitani, H.; Yokota, M.; Watanabe, T. A non-enzymatic derived arachidonyl peroxide, 8-iso-prostaglandin F2 alpha, in cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage participates in the pathogenesis of delayed cerebral vasospasm. Neurosci. Lett. 2005, 373, 222–225. [CrossRef] 131. Konczalla, J.; Vatter, H.; Weidauer, S.; Raabe, A.; Seifert, V. Alteration of the cerebrovascular function of endothelin B receptor after subarachnoidal hemorrhage in the rat. Exp. Biol. Med. 2006, 231, 1064–1068. 132. Ansar, S.; Vikman, P.; Nielsen, M.; Edvinsson, L. Cerebrovascular ETB, 5-HT1B, and AT1 receptor upregulation correlates with reduction in regional CBF after subarachnoid hemorrhage. Am. J. Physiol. Heart Circ. Physiol. 2007, 293, H3750–H3758. [CrossRef][PubMed] 133. Sakamoto, M.; Takaki, E.; Yamashita, K.; Watanabe, K.; Tabuchi, S.; Watanabe, T.; Satoh, K. Nonenzymatic derived lipid peroxide, 8-iso-PGF2 alpha, participates in the pathogenesis of delayed cerebral vasospasm in a canine SAH model. Neurol. Res. 2002, 24, 301–306. [CrossRef][PubMed] 134. Smeda, J.S.; Daneshtalab, N. The effects of poststroke captopril and losartan treatment on cerebral blood flow autoregulation in SHRsp with hemorrhagic stroke. J. Cereb. Blood Flow Metab. 2011, 31, 476–485. [CrossRef] [PubMed] 135. Tchekalarova, J.D.; Ivanova, N.M.; Pechlivanova, D.M.; Atanasovo, D.; Lazarov, N.; Kortenska, L.; Mitreva, R.; Lozanov, V.; Stoynev, A. Antiepileptogenic and neuroprotective effects of losartan in kainate model of temporal lobe epilepsy. Pharmacol. Biochem. Behav. 2014, 127, 27–36. [CrossRef][PubMed] Brain Sci. 2020, 10, 153 24 of 25

136. Sun, H.; Wu, H.; Yu, X.; Zhang, G.; Zhang, R.; Zhan, S.; Wang, H.; Bu, N.; Ma, X.; Li, Y. Angiotensin II and its receptor in activated microglia enhanced neuronal loss and cognitive impairment following pilocarpine-induced status epilepticus. Mol. Cell Neurosci. 2015, 65, 58–67. [CrossRef] 137. Tchekalarova, J.D.; Ivanova, N.; Atanasova, D.; Pechlivanova, D.M.; Lazarov, N.; Kortenska, L.; Mitreva, R.; Lozanov, V.; Stoynev, A. Long-Term Treatment with Losartan Attenuates Activity and Neuronal Damage Without Affecting Behavioral Changes in a Model of Co-morbid Hypertension and Epilepsy. Cell Mol. Neurobiol. 2016, 36, 927–941. [CrossRef] 138. Nozaki, T.; Ura, H.; Takumi, I.; Kobayashi, S.; Maru, E.; Morita, A. The angiotensin II type I receptor antagonist losartan retards amygdala kindling-induced epileptogenesis. Brain Res. 2018, 1694, 121–128. [CrossRef] 139. Biancardi, V.C.; Stranahan, A.M.; Krause, E.G.; de Kloet, A.D.; Stern, J.E. Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus. Am. J. Physiol. Heart Circ. Physiol. 2016, 310, H404–H415. [CrossRef] 140. Maeso, R.; Rodrigo, E.; Munoz-Garcia, R.; Navarro-Cid, J.; Ruilope, L.M.; Lahera, V.; Cachofeiro, V. Losartan reduces constrictor responses to endothelin-1 and the thromboxane A2 analogue in aortic rings from spontaneously hypertensive rats: Role of nitric oxide. J. Hypertens. 1997, 15, 1677–1684. [CrossRef] 141. Guan, W.; Kozak, A.; El-Remessy, A.B.; Johnson, M.H.; Pillai, B.A.; Fagan, S.C. Acute treatment with candesartan reduces early injury after permanent middle cerebral artery occlusion. Transl. Stroke Res. 2011, 2, 179–185. [CrossRef][PubMed] 142. Oku, N.; Kitagawa, K.; Imaizumi, M.; Takasawa, M.; Piao, R.; Kimura, Y.; Kajimoto, K.; Matsumoto, M.; Hori, M.; Hatazawa, J. Hemodynamic influences of losartan on the brain in hypertensive patients. Hypertens. Res. 2005, 28, 43–49. [CrossRef][PubMed] 143. Habashi, J.P.; Judge, D.P.; Holm, T.M.; Cohn, R.D.; Loeys, B.L.; Cooper, T.K.; Myers, L.; Klein, E.C.; Liu, G.; Calvi, C. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006, 312, 117–121. [CrossRef][PubMed] 144. Povlsen, G.K.; Waldsee, R.; Ahnstedt, H.; Kristiansen, K.A.; Johansen, F.F.; Edvinsson, L. In vivo experimental stroke and in vitro organ culture induce similar changes in vasoconstrictor receptors and intracellular calcium handling in rat cerebral arteries. Exp. Brain Res. 2012, 219, 507–520. [CrossRef] 145. Vikman, P.; Beg, S.; Khurana, T.S.; Hansen-Schwartz, J.; Edvinsson, L. Gene expression and molecular changes in cerebral arteries following subarachnoid hemorrhage in the rat. J. Neurosurg. 2006, 105, 438–444. [CrossRef] 146. Dimitropoulou, C.; Chatterjee, A.; McCloud, L.; Yetik-Anacak, G.; Catravas, J.D. Angiotensin, bradykinin and the endothelium. In Handbook of Experimental Pharmacology; Springer: New York, NY, USA, 2006; Volume 176, pp. 255–294. 147. Tirapelli, C.R.; Bonaventura, D.; Tirapelli, L.F.; de Oliveira, A.M. Mechanisms underlying the vascular actions of endothelin 1, angiotensin II and bradykinin in the rat carotid. Pharmacology 2009, 84, 111–126. [CrossRef] 148. Mehta, P.K.; Griendling, K.K. Angiotensin II cell signaling: Physiological and pathological effects in the cardiovascular system. Am. J. Physiol. Cell Physiol. 2007, 292, C82–C97. [CrossRef] 149. Arai, H.; Hori, S.; Aramori, I.; Ohkubo, H.; Nakanishi, S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990, 348, 730–732. [CrossRef] 150. Toda, N.; Miyazaki, M. Angiotensin-induced relaxation in isolated dog renal and cerebral arteries. Am. J. Physiol. 1981, 240, H247–H254. [CrossRef] 151. Tsutsumi, Y.; Matsubara, H.; Masaki, H.; Kurihara, H.; Murasawa, S.; Takai, S.; Miyazaki, M.; Nozawa, Y.; Ozono, R.; Nakagawa, K.; et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J. Clin. Investig. 1999, 104, 925–935. [CrossRef] 152. Abassi, Z.A.; Klein, H.; Golomb, E.; Keiser, H.R. Regulation of the urinary excretion of endothelin in the rat. Am. J. Hypertens. 1993, 6, 453–457. [CrossRef][PubMed] 153. Brunner, F.; Kukovetz, W.R. Postischemic antiarrhythmic effects of angiotensin-converting enzyme inhibitors. Role of suppression of endogenous endothelin secretion. Circulation 1996, 94, 1752–1761. [CrossRef] [PubMed] 154. Chua, B.H.; Chua, C.C.; Diglio, C.A.; Siu, B.B. Regulation of endothelin-1 mRNA by angiotensin II in rat heart endothelial cells. Biochim. Biophys. Acta 1993, 1178, 201–206. [CrossRef] Brain Sci. 2020, 10, 153 25 of 25

155. Dohi, Y.; Hahn, A.W.; Boulanger, C.M.; Buhler, F.R.; Luscher, T.F. Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries. Hypertension 1992, 19, 131–137. [CrossRef] 156. Kohno, M.; Horio, T.; Ikeda, M.; Yokokawa, K.; Fukui, T.; Yasunari, K.; Kurihara, N.; Takeda, T. Angiotensin II stimulates endothelin-1 secretion in cultured rat mesangial cells. Kidney Int. 1992, 42, 860–866. [CrossRef] 157. Saavedra, J.M.; Benicky, J.; Zhou, J. Mechanisms of the Anti-Ischemic Effect of Angiotensin II AT(1) Receptor Antagonists in the Brain. Cell Mol. Neurobiol. 2006, 26, 1099–1111. [CrossRef]

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